Journal
IMMUNITY
Volume 35, Issue 1, Pages 69-81Publisher
CELL PRESS
DOI: 10.1016/j.immuni.2011.05.010
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Funding
- Japanese-Korean Cooperative Programme on Basic Medical Research
- Joint Medical Science Research Center for the Advancement of Basic and Applied Medical Science
- Implementation of State-of-the-Art Medical Therapy
- Takeda Science Foundation.
- Grants-in-Aid for Scientific Research [21390298, 19059010, 22659097, 22500286, 22790454] Funding Source: KAKEN
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Toll-like receptor-7 (TLR7) and 9, innate immune sensors for microbial RNA or DNA, have been implicated in autoimmunity. Upon activation, TLR7 and 9 are transported from the endoplasmic reticulum (ER) to endolysosomes for nucleic acid sensing by an ER-resident protein, Unc93B1. Little is known, however, about a role for sensor transportation in controlling autoimmunity. TLR9 competes with TLR7 for Unc93B1-dependent trafficking and predominates over TLR7. TLR9 skewing is actively maintained by Unc93B1 and reversed to TLR7 if Unc93B1 loses preferential binding via a D34A mutation. We here demonstrate that mice harboring a D34A mutation showed TLR7-dependent, systemic lethal inflammation. CD4(+) T cells showed marked differentiation toward T helper 1 (Th1) or Th17 cell subsets. B cell depletion abolished T cell differentiation and systemic inflammation. Thus, Unc93B1 controls homeostatic TLR7 activation by balancing TLR9 to TLR7 trafficking.
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